DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claims 1-13, 15-16 and 18-24 are pending in this application, Claims 7-13, 15, 16 and 18-22 are acknowledged as withdrawn, Claims 1-6, 23 and 24 were examined on their merits.
The rejection of Claims 1-6 under 35 U.S.C. § 112(b) or 35 U.S.C. § 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention, has been withdrawn due to the Applicant’s amendments to the claims filed 09/14/2026.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claim(s) 1-6, 23 and 24 are newly rejected under 35 U.S.C. § 103 as being unpatentable over Selahi et al. (2019) in view of Fathi et al. (2020), both of record, as necessitated by Applicant’s amendments to the claims filed 09/14/2026.
Selahi et al. teaches an in vitro lymphatic vessel model, comprising providing a
microfluidic substrate extending along a longitudinal axis and defined by an inner
surface (microfluidic channel/passage),
and co-culturing a plurality of first (lymphatic endothelial cells/LEC) and second
cells (lymphatic muscle cells/LMC) whereby an annular inner layer of the LEC and an
annular outer layer of the LMC defines a lumen extending longitudinally through the
microfluidic channel/passage, wherein the lumen has a circular (therefore elliptical) cross-section (Abstract and Fig. 1), and reading on Claims 1, steps a) and c), 2, 3 and 4.
Selahi et al. further teaches that the annual layer of the plurality of lymphatic endothelial cells is distributed substantially uniformly about the circumference of the microfluidic channel/passage (as depicted in Fig. 1) and that it is possible to construct a wide range of luminal diameters and vessel muscular layer thicknesses (Abstract).
Selahi et al. did not teach a method wherein the microfluidic channel is
positioned in a vertical orientation forming an acute angle of less than or equal to 30° or 10° between the longitudinal axis of the microfluidic channel and the direction of gravity, as now required by Claim 1, step b) and Claim 23;
culturing a plurality of first cells in the microfluidic passage while the substrate is disposed in the vertical orientation whereby an annular layer of the plurality of first cells is formed in the microfluidic channel/passage and distributed substantially uniformly about a circumference of the microfluidic channel/passage, wherein the layer of the plurality of first cells defines a lumen extending longitudinally through the microfluidic channel/passage, as now required by Claim 1, step c);
the sequential steps of:
forming a substrate that defines a microfluidic passage therein extending along a longitudinal axis and defined by an inner surface;
culturing a plurality of second cells that are different from a plurality of first cells in the microfluidic passage whereby an annular layer of the plurality of second cells is formed in the microfluidic channel/passage;
positioning the substrate in a vertical orientation whereby an acute angle of less than or equal to 30° is formed between the longitudinal axis of the microfluidic passage and the direction of gravity; and
culturing a plurality of first cells in the microfluidic passage while the substrate is disposed in the vertical orientation whereby an annular layer of the plurality of first cells is formed in the microfluidic channel/passage and distributed substantially uniformly about a circumference of the microfluidic channel/passage, wherein the layer of the plurality of first cells defines a lumen extending longitudinally through the microfluidic channel/passage, as now required by Claim 5;
wherein a ratio of a major axis of the elliptical cross-section to a minor axis of the elliptical cross-section is between 1.1:1 and 5:1, as now required by Claim 6;
or wherein a ratio of a minimum radial thickness of the annular layer to a maximum radial thickness of the annular layer is between 0.5:1 and 2:1, as now required by Claim 24.
With regard to Claim 6, Selahi et al. teaches a lumen extending longitudinally through the microfluidic channel/passage, wherein the lumen has a circular (therefore elliptical) cross-section. Since it is circular the ratio of the major axis to minor axis of the circle’s cross section is 1:1, which is sufficiently close to the claimed ratio of 1.1:1, such that they would be expected to have the same properties. See the MPEP at 2144.05, I.
Fathi et al. teaches an in vitro model of lymphatic vessels comprising a substrate having microfluidic channels wherein LEC cells are cultured at an acute angle (45°) between the longitudinal axis of the microfluidic channel and the direction of gravity (Pg. 6703-6704, Paragraphs 4.1, 4.2, 4.4.3 and 4.5 and Pg. 6698, Fig. 1);
wherein the device can be set to angles between 0 and 90° to control the flow rates and resulting shear stress in the device (Pg. 6701, Column 1, Lines 1-3 and Pg. 6698, Fig. 1D);
and wherein the device utilizes a gravity driven flow which provides the ability to obtain the desired shear stresses without the need for an active pumping mechanism, allows for the simultaneous operation of multiple devices,
thereby reducing the cost of adopting such tissue-on-a-chip technologies, and the use of unidirectional flow serves as a physiologically accurate mimic of flow in the lymphatic system (Pg. 6698, Column 1, Lines 11-21).
It would have been obvious to those of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of Selahi et al. of preparing an in vitro model of lymphatic vessels comprising co-culturing a plurality of first (lymphatic endothelial cells/LEC) and second cells (lymphatic muscle cells/LMC) in a microfluidic channel to perform the culturing wherein the microfluidic channel is positioned in an orientation forming an acute angle between the longitudinal axis of the microfluidic channel and the direction of gravity as taught by Fathi et al. because this would provide a more realistic in vitro approximation of the effects of gravity and flow in the lymphatic system. Those of ordinary skill in the art would have been motivated to make this modification because Fathi et al. teaches the method advantageously utilizes a gravity driven flow which provides the ability to obtain the desired shear stresses without the need for an active pumping mechanism, allows for the simultaneous operation of multiple devices, thereby reducing the cost of adopting such tissue-on-a-chip technologies, and the use of unidirectional flow serves as a physiologically accurate mimic of flow in the lymphatic system. There would have been a reasonable expectation of success in making this modification because both references are reasonably drawn to the same field of endeavor, that is, in vitro cell-based models of lymphatic vessels.
While the Fathi reference does not specifically teach the limitations of the
substrate being positioned in a vertical orientation (e.g. given the broadest reasonable
definition of being perpendicular to the horizon or level surface) having an acute angle of less than or equal to 30 or 10°, one of ordinary skill in the art would recognize that the device angle during culturing is a result-effective optimizable variable. Fathi et al. teaches that the device can be set to angles between 0 and 90° (e.g. vertical and encompassing the claimed angle parameters) to control the flow rates and resulting shear stress in the device. This is motivation for someone of ordinary skill in the art to practice or test the angle values widely to find those that are functional or optimal for the desired cell culture modeling of lymphatic vessels, which then would be inclusive or cover that values as instantly claimed. Absent any teaching of criticality by the Applicant concerning the verticality of the device, it would be prima facie obvious that one of ordinary skill in the art would recognize these limitations are an optimizable variable which can be met as a matter of routine optimization (see MPEP § 2144.05 (II)(B).
With regard to Claim 24, while the Fathi reference does not specifically teach the limitations of the ratio of the minimum radial thickness of the annular layer to a maximum radial thickness of the annular layer being between 0.5:1 and 2:1, one of ordinary skill in the art would recognize that the ratio of the minimum to maximum radial thickness of the annular layer is a result-effective optimizable variable. Selahi et al. teaches that it is possible to construct a wide range of luminal diameters and vessel muscular layer thicknesses. Thus, it would also be possible to prepare a wide range of annular layer radial thicknesses which would inherently have ratios between their minima and maxima. This is motivation for someone of ordinary skill in the art to practice or test the annular layer radial thickness values widely to find those that are functional or optimal for the desired cell culture modeling of lymphatic vessels, which then would be inclusive or cover that values as instantly claimed. Absent any teaching of criticality by the Applicant concerning the ratio of the minimum radial thickness of the annular layer to a maximum radial thickness of the annular layer, it would be prima facie obvious that one of ordinary skill in the art would recognize these limitations are an optimizable variable which can be met as a matter of routine optimization (see MPEP § 2144.05 (II)(B).
It would have been further obvious to those of ordinary skill in the art before the
effective filing date of the claimed invention to modify the method of Selahi et al. and
Fathi et al. wherein a first and second plurality of cells (LEC and LMC) are co-cultured in
the microfluidic channel forming an annular layer to instead culture the second plurality of cells (LMC) and form an annular layer in the microfluidic channel prior to culturing a plurality of cells (LEC) and forming an annular layer that defines a lumen extending longitudinally through the microfluidic channel because the selection of any order of culturing the cells is prima facie obvious in the absence of new or unexpected results. See the MPEP at 2144.04, IV, C. Those of ordinary skill in the art would have been motivated to make this modification in order to form a desired order of cell layers in a coculture. There would have been a reasonable expectation of success in making this modification because the reference already teaches coculturing two cells types and Fig. 1 of Selahi which depicts an outer layer of LMC surrounding an inner layer of LEC
is suggestive of a particular order of culturing the cells to form the coculture.
Response to Arguments
Applicant’s arguments, see Remarks, filed 09/14/2026, with respect to the above withdrawn rejection have been fully considered and are persuasive. The remaining arguments have been considered insofar as they apply to the current rejections.
The Applicant argues that neither Selahi or Fathi teach or suggest the limitations of amended Claim 1. Applicant notes that Selahi does not disclose the orientation angle of its’ device to gravity or the effect thereof on the resulting cell layer. Applicant further notes that Fathi discloses a device for culturing a monolayer of LEC on a channel and does not disclose co-culturing or an annular lumen. Applicant asserts that Fathi discloses a preferred embodiment of 45° and does not mention circumferential distribution of a cultured cell layer, lumen shape or symmetry (Remarks, Pg. 6, Lines 32-35 and Pg. 9, Lines 1-21).
This is not found to be persuasive for the following reasons, as discussed above, the combination of Selahi in view of Fathi makes obvious the claimed invention. Selahi discloses the co-culturing of lymphatic endothelial cells and lymphatic muscle cells as an in vitro model of lymphatic vessels, the formation of a lumen thereof, as well as the shape and symmetry thereof. Fathi was cited for its’ teaching of an in vitro model of lymphatic vessels comprising a substrate having microfluidic channels wherein LEC cells are cultured at an exemplary acute angle (45°) between the longitudinal axis of the microfluidic channel and the direction of gravity (Pg. 6703-6704, Paragraphs 4.1, 4.2, 4.4.3 and 4.5 and Pg. 6698, Fig. 1), wherein the device can be set to angles between 0 and 90° to control the flow rates and resulting shear stress in the device (Pg. 6701, Column 1, Lines 1-3 and Pg. 6698, Fig. 1D);
and wherein the device utilizes a gravity driven flow which provides the ability to obtain the desired shear stresses without the need for an active pumping mechanism, which allows for the simultaneous operation of multiple devices thereby reducing the cost of adopting such tissue-on-a-chip technologies, and the use of unidirectional flow serves as a physiologically accurate mimic of flow in the lymphatic system (Pg. 6698, Column 1, Lines 11-21). Therefore, it would have been obvious to those of ordinary skill in the art to modify the method of Selahi of preparing an in vitro model of lymphatic vessels comprising co-culturing a plurality of first (lymphatic endothelial cells/LEC) and second cells (lymphatic muscle cells/LMC) in a microfluidic channel to perform the culturing wherein the microfluidic channel is positioned in an orientation forming an acute angle between the longitudinal axis of the microfluidic channel and the direction of gravity as taught by Fathi because this would provide a more realistic in vitro approximation of the effects of gravity and flow in the lymphatic system (e.g. based on shear stress arising from natural unidirectional flow and not pumping).
The Applicant argues the Specification provides context for the claims noting the conventional culture of an in vitro vessel in an orientation such that the force of gravity draws cells from the top of a lumen/passage to the bottom resulting in a thick bottom layer and thin top cell layer while the claimed invention provides a device in which gravity acts in a direction parallel to the longitudinal axis of the vessel and provides a uniform distribution of luminal cells. Applicant asserts the cited prior art does not provide this feature (Remarks, Pg. 10, Lines 1-20).
This is not found to be persuasive for the following reasons, although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). In this instance, as discussed above, the combination of Selahi in view of Fathi makes obvious the co-culture of a plurality of first (lymphatic endothelial cells/LEC) and second cells (lymphatic muscle cells/LMC) in a microfluidic channel wherein the microfluidic channel is positioned in an orientation forming an acute angle between the longitudinal axis of the microfluidic channel and the direction of gravity. Selahi et al. further teaches that the annual layer of the plurality of lymphatic endothelial cells is distributed substantially uniformly about the circumference of the microfluidic channel/passage (Fig. 1).
The Applicant argues that neither Selahi or Fathi recognize that altering the vertical orientation of the substrate affects the claimed parameter of a uniform distribution of a first type of cells about the circumference of a microfluidic passage/channel. Applicant opines that absent such recognition, the disclosed orientation range of Fathi as subject to routine optimization is based on improper hindsight (Remarks, Pg. 10, Lines 21-31).
In response to Applicant's argument that the Examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning.
But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the Applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). In this instance, Fathi recognizes the beneficial aspects of altering the orientation angle of the culture substrate in an in vitro model of lymphatic vessels. The reference further recognizes that any angle between 0 and 90° may be used in said orientation to control the flow rates and resulting shear stress in the device. Thus, one of ordinary skill in the art would recognize that the device angle during culturing is a result-effective optimizable variable. This is motivation for someone of ordinary skill in the art to practice or test the angle values widely to find those that are functional or optimal for the desired cell culture modeling of lymphatic vessels, which then would be inclusive or cover that values as instantly claimed. Absent any teaching of criticality by the Applicant concerning the verticality of the device, it would be prima facie obvious that one of ordinary skill in the art would recognize these limitations are an optimizable variable which can be met as a matter of routine optimization (see MPEP § 2144.05 (II)(B). As noted above, Selahi already achieves the claimed parameter of a uniform distribution of a first type of cells about the circumference of a microfluidic passage/channel. Nevertheless, in response to Applicant's argument that the cited prior art allegedly does not achieve this result, the fact that the inventor has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious. See Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985).
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the Examiner should be directed to PAUL C MARTIN whose telephone number is (571)272-3348. The Examiner can normally be reached Monday-Friday 12pm-8pm EST.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, Applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the Examiner by telephone are unsuccessful, the Examiner’s supervisor, Sharmila G Landau can be reached at (571) 272-0614. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/PAUL C MARTIN/ Examiner, Art Unit 1653
/SHARMILA G LANDAU/ Supervisory Patent Examiner, Art Unit 1653
